Evaluation of multikinase inhibitor LDN193189 induced hepatotoxicity in teleost fish Poecilia latipinna

Abstract

Currently, scientists show keen interest in the drugs that inhibit multiple kinases, LDN193189, being an example. It combats certain cancers in vitro as well as in vivo, making it a prerequisite for researchers to study the toxic potential of this drug in animal models. As most of the drugs metabolized by liver cause hepatic injury, LDN193189-induced hepatotoxicity was examined using a teleost fish, Poecilia latipinna. As a prelude, calculation of LD₅₀ showed a value of 95.22 mg/kg body weight and three doses were decided based on it for further evaluations. All these groups were tested for antioxidant enzyme levels and were significantly raised for mid- and high-dose group. Similar trend was recorded for ALP, AST, and ALT levels. Furthermore, some key indicators of drug metabolism in liver were tested for their expression in response to LDN193189 treatment. Among these, Cyt-C, CYP3A4, CYP1B1 and CYP1A1 were elevated in mid- and high dose, except CYP21A1, which declined remarkably. Moreover, histological profile of the liver reflected high degree of inflammation due to drug treatment, but this was found only at high dose. In summary, LDN193189, at 2.5 mg/kg body weight, did not cause any adverse hepatotoxicity, rendering it safe for use as an anti-proliferative agent – an activity for which it has already shown promising results in the same animal model. The low-dose group previously studied for its anti-proliferative property showed no adverse effect in liver, whereas the mid- and high dose induced moderate or severe hepatotoxicity in P. latipinna.

Keywords:

• LDN193189
• Poecilia latipinna
• hepatotoxicity
• antioxidant
• CYP450
• histopathological alteration index
• cholestatic hepatitis

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

The authors are thankful to Department of Biotechnology, New Delhi [grant No. BT/PR11467/MED/31/270/2014] for financial support for this research study. I.R. and S.P. are thankful to DST-SERB, New Delhi and University Grants Commission, respectively, for their support in form of fellowship.